Project Summary/Abstract This is a revised application of a competing renewal R01 originally funded by the RFA DK-03-010 entitled: "Basic Research in Interstitial Cystitis". Mycobacterium bovis bacillus Calmette-Gu[unreadable]rin (BCG) has long been demonstrated to be a potent stimulator of immune response. Its anti-cancer effect has been exploited in the therapy of superficial bladder cancer and it is a promising option for the treatment of interstitial cystitis (IC). Despite a long history of successful application of BCG, the existence of a 30% non-response rate in BCG therapy of bladder cancer and a safe but low rate of response in IC patients remains a concern. Following this initial observation, several additional IC trials were performed which showed that subsets of patients may benefit from BCG therapy. This suggests a need for a better understanding on the basic mechanisms of BCG's action as well as possible reactions of the organism limiting the response to BCG. The initial grant period successfully unveiled key mechanisms underlying intravesical BCG therapy that compose the central hypothesis of the present application: Intravesical BCG treatment elicits several mechanisms that can limit the access and survival of BCG in the urinary bladder, including: 1) down regulation of uroplakins that may be part of the uptake mechanism of BCG;2) p47GTPases that will target BCG for degradation;and 3) IL-17 a cytokine that will elicit a strong inflammatory response incompatible with a therapeutic effect of BCG. Understanding how these basic mechanisms contribute to the overall efficacy of BCG treatment and confirming possible targets in specimens from human subjects treated with BCG will provide valuable tools to be used as co-adjuvant therapies